chapter 9

Annals of Oncology 18 (Supplement 1): i49i53, 2007

doi:10.1093/annonc/mdl451

Management of elderly patients with hematological

neoplasms
O. Mora & E. Zucca
IOSI, Oncology Institute of Southern Switzerland, Medical Oncology Department, Ospedale San Giovanni, Bellinzona, Switzerland

Persons >65 years represent the fastest growing segment of the

population in Western countries. Estimates for the European
Union suggest by 2015 a 22% increase in people older than 65
years and 50% increase in those older than 80 years.
Cancer incidence in general increases with age and more than
half of all new cancers occur in patients 65 years of age or older.
The incidence of cancer in the population >65 years is >10 times
higher than in the population <65 years and more than half of
all cancer-related deaths occur in elderly patients.
Appropriately, the problem of cancer in the elderly has been
defined as an oncological time bomb.
Hematological neoplasms do not escape this age-related
increase in tumor incidence, which holds true for nonHodgkins lymphomas, multiple myeloma and all leukemia
subtypes, with the exception of acute lymphoblastic
leukemia (ALL).
In addition, the prognosis of most hematological tumors
worsens with age (e.g. acute myelogenous leukemia, large-cell
non-Hodgkins lymphoma). Nevertheless, these tumors are
often potentially curable and this poses specific problems to the
physicians dealing with elderly people.
Nowadays, older persons in most European and North
American countries enjoy good health for a longer period than
previously realized, and many factors that may compromise
fitness in the elderly (e.g. chronic diseases, poor vision, hearing
loss and depression) can be easily addressed and often modified.
Therefore, a long period of worsening illness and disability
is no longer necessarily part of normal aging. With the
increasing number of otherwise healthy older patients with
(hematological) cancer, the chronological age cannot anymore
be a criterion for justifying or denying access to a potentially
curative but toxic therapy. Any preliminary clinical evaluation
of elderly patients with cancer should also be aimed to
distinguish the frail patients from the otherwise healthy ones.
While cancer diagnosis is likely to decrease life expectancy in
the majority of younger patients, the same consideration may
not be true in older people. Life expectancy (the average
numbers of remaining years of life) in elderly cancer patients is
a function of age, disability and co-morbidity, along with the
cancer type and stage (Table 1).
Therapeutic decision making involves a delicate balance
among all these factors, evaluation of treatment-related
complications and the overall effects of cancer and cancer
2007 European Society for Medical Oncology

treatment on the patients expected survival and quality of life.

Therefore, the treatment choice must be tailored to the
condition of the individual patient. The following questions
should be addressed before any treatment decision: whether
the patient is likely to die with tumor or because of it,
whether the patient is expected to suffer severe cancer-related
morbidity, and whether the patient is likely to tolerate a curative
treatment and its complications.
In fact, age in itself should not be a barrier to full-dose cancer
treatment. However, the proportion of elderly patients enrolled
in registration trials decreases with age: 38% for patients older
than 65 years, 20% for those older than 70 years and 10% for
those >75 years. This underrepresentation in studies is most
likely reflected in undertreatment in clinical practice. This may
be a very relevant issue when dealing with tumors that can be
cured.

geriatric assessment in cancer patients

assessment of aging
Chronological age is a well-established prognostic factor for
lymphomas and leukemias, and can be the easiest and most
reproducible way to estimate the extent of aging, but this is not
always appropriate because life expectancy depends on the
individuals general health. Although it is impossible for
physicians to predict the exact life expectancy of an individual
patient, it is nevertheless possible to make reasonable estimates
of whether a patient is likely to live substantially longer or
shorter than an average person in his/her age cohort (Table 1).
assessment of disability
Measures of performance status (PS) [the Karnofsky and
Eastern Cooperative Oncology Group (ECOG) scales] are
usually designed for use in patients with cancer but are not
specific to the elderly.
The ECOG PS is a simple functional score that rates
functional status from 0 (normal activity) to 4 (bedridden) and
it has proven to be a powerful independent prognostic predictor
in cancer patients. Impairment of PS in elderly patients is likely
not to be uniquely cancer related.
Geriatricians have developed a variety of scoring systems such
as the Barthel index, the activities of daily living scale (ADL)
and the instrumental activities of daily living scale (IADL) for

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Table 1 Life expectancy in the elderly in western countries according to

age and sex
Age (year)

Median life expectancy (50th percentile)

Women
Men

65
70
75
80
85
90
95

19
16
12
9
6
4
3

15
12
9
7
5
3
2

the functional evaluation of their patients but these tools are

not specific for cancer.
The Barthel index and the ADL scale evaluate the basic
functional activities. Using ADL, six functions are measured:
incontinence, bathing, dressing, toileting, transferring, and
feeding. The instrument has three descriptions for each
function: independent, assisted, and dependent functioning.
The IADL scale measures more elaborate functions. The scale
consists of nine items: ability to use the telephone, shopping,
food preparation, housekeeping, handyman work, laundry,
mode of transportation, responsibility for own medications, and
ability to handle finances. Responses to each item range from
independent to moderately independent to dependent.

assessment of co-morbidity
Co-morbidity is one of the most visible differences between
younger and older individuals and may interfere with diagnosis
and treatment of cancer even if it is often difficult to distinguish
the results of concomitant illness conditions from the disability
from cancer and cancer treatment side-effects. Furthermore,
cancer treatment can worsen co-morbidity.
There is no clear consensus about the number and types of
conditions that should be included in co-morbidity assessment,
and the most commonly used index in geriatric medicine (i.e.
the Charlson index, which includes 19 selected conditions) can
be difficult to use in an oncohematological setting. Nevertheless,
proper attention should be paid to the most frequent co-morbid
diseases and to those that can become life threatening or
difficult to control (e.g. arrhythmias and congestive heart
failure, chronic obstructive pulmonary disease, insulindependent diabetes, chronic liver disease, renal insufficiency,
gastrointestinal problems, osteoporosis). In addition to the
concurrent presence of chronic conditions, older individuals
may carry common geriatric syndromes such as those related
to dementia, incontinence, malnutrition, depression, imbalance
and gait disorders.
comprehensive geriatric assessment
This type of assessment derives from the idea that older
individuals may represent as unique a cohort of patients as do
children, for whom an entire discipline (pediatrics) exists.
Comprehensive geriatric assessment (CGA) has been defined
as a multidisciplinary evaluation in which the multiple

i50 | Mora & Zucca

problems of older persons are uncovered, described, and

explained, if possible, and in which the resources and strengths
of the person are catalogued, need for services assessed, and
a coordinated care plan developed to focus interventions on the
persons problems.
It is aimed to evaluate together the socioeconomic condition,
the functional and nutritional status, the co-morbidity with the
presence or absence of geriatric syndromes, and the need of
medications.
CGA can provide a common language for classifying the
physiologic age of older cancer patients. It may provide
a common basis in outcome research. It may be used as a basis
for the choice of cancer treatment in specific clinical situations.
Because most oncologists have limited time and little
experience with the geriatric assessment and geriatricians may
not be readily available, not all patients should or could undergo
an extensive geriatric assessment. It should anyway be kept in
mind that a proper geriatric assessment could be important
especially to recognize the frail patient and to direct treatmentrelated decisions. Therefore, some type of screening is
recommended and should be aimed at evaluating mental status
and emotional status, PS and daily activities (ADL and IADL),
home environment, social support, co-morbidity, nutrition
status, and polypharmacy. However, it is difficult to provide
a simple general schema.

how to identify the frail patient

Identification of older frail patients with a critical reduction in
functional reserve that makes them unsuitable for the standard
forms of aggressive treatment of either severe [such as
daunorubicin and cytarabine in acute myeloid leukemia
(AML)] or limited toxicity (such as R-CHOP for large-cell
lymphomas) is critical in hematological oncology.
Several definitions of frailty have been formulated, all on the
basis of the main concept that frailty implies a critical reduction
in functional reserve with limited ability to withstand even
the most ordinary stresses.
Frailty is common in the last span of human life preceding
death but it is not synonymous with imminent death. In fact, the
average life expectancy of the frail patient is 2 years. A practical
definition of the frail elderly patient can be provided by the
presence of

dependence in one or more activities of daily living (bathing,

dressing, toileting, continence, mobility, and feeding)
or three or more co-morbid conditions
or one or more geriatric syndromes.

It is not clear whether any age level should be considered

a criterion of frailty but it is advisable to consider age >85 if
not a frailty indicator itself at least as a warning to look for
the above listed signs of frailty.

changes of pharmacology parameters

in the elderly
Physiologic modifications of body function are known to
occur with age and may interfere with cancer treatment. The

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decreasing renal excretion of drugs is the most predictable

change: the glomerular filtration rate declines consistently
with age by 1 ml/min/year from the age of 40 years. The
hepatic function is also modified in older patients with
decrease in liver size, blood flow, albumin production, and
cytochrome P450 function. These changes have important
impact on the pharmacokinetic processes of absorption,
distribution, metabolism, and excretion and the
pharmacodynamic properties of administered drugs. They
can lead to opposite and potentially harmful consequences,
such as excessive drug concentrations and unacceptable
toxicity or suboptimal drug concentration and ineffective
treatment.
Moreover, an increased intake of concomitant medications in
the elderly may result in drugdrug interactions by competition
for serum albumin-binding sites or the cytochrome P450
enzymes.
There are several pharmacological parameters that can be
taken into account when treating elderly patients with
anticancer drugs: oral absorption, volume distribution, body
composition (decline in body water and increase in body fat),
serum albumin, hemoglobin level, liver metabolism, renal
excretion, biliary excretion, and drug interactions.
However, despite the increased susceptibility of the elderly
to these changes, doses of anticancer drugs are rarely adapted
on the basis of the pharmacokinetics and pharmacodynamics,
with the exception of changes secondary to altered renal
function.
Additionally, older patients appear to be at special risk for
severe and prolonged myelodepression and mucositis, at
increased risk for chemotherapy-associated cardiomyopathy as
well as for central and peripheral neuropathy.
Some threats may be prevented or reduced. For example,
myelosuppression can be very severe; however, the use of
growth factors [granulocyte colony-stimulating factor (G-CSF)]
in fact can allow administration of curative chemotherapy doses
in many elderly patients. Particular attention should be given to
anemia, which causes fatigue that may ultimately precipitate
functional dependence, especially in those elderly patients who
are already dependent in their instrumental activity of daily
living.

treatment of hematological neoplasms

in the elderly
defining the aim of cancer therapy in
the elderly patient
The frail person needs individualized treatment plans and is not
a candidate for aggressive life-prolonging cancer treatment but
can be a candidate for aggressive symptom palliation. Common
symptoms of hematological neoplasms include pain, especially
bone pain, anemia, fatigue, and bleeding. Anti-neoplastic
treatment is very often pivotal to symptom palliation and the
best supportive care may involve cytotoxic chemotherapy.
Hence, it is very important to define the aim of the
chemotherapy before commencing treatment in elderly cancer
patients.
In frail patients, or patients with considerable co-morbidity,
supportive care only is often the best action even when tumors
are potentially curable and the goal is the quality of life. In this
group, the toxicity of cancer treatment is generally not
acceptable and strong efforts should be made to avoid it.
In the curative setting, it is important to try to maintain dose
intensity because there is a steep doseresponse curve, and a
small decrease in dose intensity can lead to a significant
decrease in cure rates. In this situation, some toxicity is
acceptable but it must be very carefully managed.
The aforesaid considerations should be always taken into
account and Table 2 summarizes some practical tips but the
specific problems posed by each hematological neoplasm should
not be overlooked.
acute leukemias in the elderly
Age is a main prognostic factor in both ALL and AML. ALL is
rare in elderly people but the majority of patients with AML are
60 years of age or older and the number of patients is increasing.
While many younger adults with AML can be cured, the
outcome of elderly people remains unsatisfactory, with 10% of
survival rates at 5 years. High-dose chemotherapy is not
beneficial in elderly patients with AML and the patients >60
years of age have significantly lower remission rates (50% versus
75%) than the younger patients as well as a three times higher

Table 2 Some practical suggestions for the management of the older patients with hematological neoplasms
Careful selection of patients suitable for curative therapy
Some geriatric assessment is strongly advisable for all patients >65 years to identify the frail patients unfit for aggressive regimens
Treat co-morbidity aggressively
Manage in advance any conditions that may interfere with cancer chemotherapy (e.g. polypharmacy, risk of malnutrition, absence of reliable care giver)
Pharmacological interventions
Adjust dose of chemotherapy to the renal function, to the nadir count, and to other complications
Maintain good hemoglobin levels (>10 g/dl) when needed with the use of erythropoietin
Use G-CSF prophylaxis in patients aged 70 years and older receiving chemotherapy of moderate toxicity (e.g. CHOP)
Consider use of prophylactic antibiotics in patients who may be neutropenic for a week or longer
Consider less toxic alternatives to doxorubicin when equal effectiveness has been demonstrated
In frail patients, consider reducing the initial dose of anticancer agents (especially those that are metabolized in the liver)
Clinical interventions
Treat mucositis aggressively and correct promptly fluid and electrolyte imbalances
Perform neurological examination at each clinic visit to early detect neuropathy

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risk of treatment-related death (30% versus 10%). In this
scenario, intensive chemotherapy with curative aim can be the
treatment of choice only for those patients <80 with good
prognostic features (i.e. favorable karyotype, no antecedent
myelodysplasia, no major co-morbid conditions, and good PS)
who are well motivated to take the risk of toxic treatment. The
other patients will probably benefit more from palliative
hematological treatment aimed at the best possible quality of
life. Similar considerations can be applied to the few elderly
patients with ALL.

myelodysplastic syndromes
Myelodysplastic syndromes (MDSs) comprise a group of
hematological neoplasms, manifesting as cytopenias that occur
almost exclusively in the elderly population. Anemia,
neutropenia, and thrombocytopenia may occur either alone or
in combination and there is, by definition, no underlying
systemic illness to account for them.
The possibility of cure is restricted to a tiny minority of young
patients, with compatible donors, for whom allogeneic stem-cell
transplantation is the treatment of choice. In general, however,
intensive treatment is considered ineffective and
contraindicated in MDS patients. Low-dose chemotherapy may
help controlling the peripheral leucocytosis (subcutaneous
cytarabine, oral etoposide, 6-mercaptopurine, and 6thioguanine can all be effective) but does not alter the long-term
outcome. Supportive care, therefore, with blood products
combined with broad-spectrum antibiotics remains the
cornerstone of therapy for elderly patients. Recently, the
combination of G-CSF and erythropoietin has been shown to
improve anemia and neutropenia in some patients.
chronic myeloid leukemia in older people
The age of the majority of patients diagnosed with chronic
myeloid leukemia (CML) is 65 years or older and, because of
age-related additional medical problems, until recently most
elderly patients were considered to have in general a poor
prognosis.
This is no longer true after the introduction of the
molecularly targeted therapy with imatinib mesylate. Patients
aged 60 or older appear to benefit from treatment with imatinib
as much as younger patients and increased age does not
anymore appear to be necessarily an indicator of unfavorable
prognosis of CML.

treatment of aggressive lymphomas in

the elderly
Most non-Hodgkins lymphoma subtypes display a peak of
incidence in the age group >60. The most common aggressive
subtype is diffuse large B-cell lymphoma. Age has been
recognized as a major risk factor for the overall survival of
diffuse large-cell lymphoma patients, and several factors may
contribute to the age-related worsening of outcome (different
tumor biology, age-related immunodeficiency, age-specific comorbidity, limited ability to tolerate intensive chemotherapy,
and socioeconomic factors).

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Annals of Oncology

Several studies report increased toxicity of cytotoxic drugs in

elderly patients: cardiotoxicity of anthracyclines; hematological
toxicity of adriamycin, methotrexate, etoposide, and
vinblastine; and pulmonary toxicity of bleomycin and
mucositis.
Nevertheless, in recent years large randomized clinical trials
have demonstrated that intense treatment with a curative intent
can be successfully given even in the very elderly, provided that
the proper supportive care is given, especially G-CSF
administration to prevent infections and to allow
administration of full-dose therapy without delays between the
chemotherapy courses. These studies have shown that
combining chemotherapy and anti-CD20 monoclonal
antibodies seems to be the main optional strategy, and older
non-frail patients can be treated with the same intensive
approaches that were usually reserved for younger patients. This
may result in response, event-free survival, and overall survival
rates similar to those observed in their younger counterparts.
Many elderly patientsif not frailcan get successful salvage
treatment at relapse, too. Autologous transplantation of
peripheral blood stem cells is the treatment of choice and the
procedure is nowadays usually offered up to 65 years of age.

indolent lymphomas and CLL

These entities afflict almost exclusively adults, particularly the
middle-aged and elderly. Both the incidence and the associated
mortality rates have increased over the past 20 years in elderly
persons. An age >70 years has a negative impact on outcome,
but the contribution of concomitant diseases herein is very
important. Indeed, these diseases have most often a very
indolent course and the median survival exceeds 10 years in
most reported series. In spite of the recently reported survival
improvements, achieved with the addition of the anti-CD20
monoclonal antibodies to the therapeutic armamentarium
against low-grade lymphomas, or with timely peripheral blood
stem-cell transplantation, none of the currently available
treatment regimens have yet been shown able to alter the natural
history of these diseases in elderly people.
Neither single-alkylating agent chemotherapy nor aggressive
combination regimens, even when combined with monoclonal
antibodies, can cure advanced-stage low-grade non-Hodgkins
lymphomas and CLL. An initial policy of watchful waiting in
asymptomatic patients is often appropriate, especially in
patients older than age 70 years since aggressive therapy will not
improve survival.
The decision to start therapy is on the basis of the stage of the
disease, the occurrence of disease-associated symptoms,
including B symptoms, recurring infections, autoimmune
anemia or thrombocytopenia, pancytopenia associated with
bone marrow infiltration, bulky disease causing discomfort,
impairment of organ function, and hypersplenism.
Hodgkins lymphoma
In western countries, the incidence of Hodgkins lymphoma
(HL) shows a bimodal age distribution with a main peak in the
early adulthood and a second peak around the sixth decade.
With improved prognosis of HL, interest increasingly focuses on
high-risk groups such as elderly patients. In general, elderly

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patients with HL have a less favorable prognosis than do

younger ones.
In a retrospective analysis of the German Hodgkins Study
Group, elderly patients more often had mixed-cellularity
subtype, B symptoms, elevated erythrocyte sedimentation
rate, and poorer PS. Acute toxicity during chemotherapy was
generally higher in elderly patients, especially severe leucopenia
resulting in higher rates of severe infections. Significantly, fewer
elderly patients received the intended full chemotherapy dose
and the survival analysis showed a significantly poorer survival.
Higher mortality during treatment as well as lower dose
intensity, often due to decreased tolerance to treatment and comorbid conditions, contributes to the poor outcome. Comorbidity is often a prognostic factor more important than age
itself. Nevertheless, most elderly patients can be cured if after
comprehensive assessment before treatment; proper attention is
then paid to the choice of a chemotherapy regimen with
a favorable toxicity profile, to the careful monitoring of toxicity,
and to the prompt administration of adequate supportive care.

multiple myeloma
Multiple myeloma is predominantly a disease of the elderly with
a median age at diagnosis of 65 years and its incidence appears

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increasing with age, and age >65 years has been identified as an
adverse prognostic factor.
Therapy should be delayed in multiple myeloma until the
patient is symptomatic, while patients with smoldering
myeloma and MGUS should not be treated. An increasing
M-protein in the serum or urine, development of anemia,
hypercalcemia, renal insufficiency, and/or the development of
lytic lesions are common indications for treatment.
Increasing evidence indicates that the approach to treatment
in multiple myeloma in the elderly with good PS and a lack of
severe co-morbidities should follow the same guidelines applied
to younger individuals. Reviews of treatment outcomes
following transplantation in myeloma have concluded that age
alone (<70 years) is not a prognostic variable and should not
exclude a patient from consideration for high-dose therapy.
In frail patients with relevant co-morbidities, oral
chemotherapy with single alkylating agent, melphalan, is often
feasible in the majority of patients. The last decade has seen the
development and use of a number of novel effective drugs for
myeloma such as thalidomide that is very active in combination
with dexamethasone and bortezomib. They may be safely used
in most elderly patients, provided that proper attention is paid
to their non-hematological toxicity.

doi:10.1093/annonc/mdl451 | i53